Bleeding is a common clinical problem in trauma, surgery, bleeding disorders, stroke, menorrhagia and liver diseases. Treatment of bleeding includes agents in primary and secondary haemostasis as well as fibrinolysis inhibition.
The fibrinolytic system comprises an inactive zymogen, plasminogen (PLG), that can be activated to the active enzyme plasmin (PLN). PLN degrades insoluble fibrin into soluble fibrin fragments. The result of this activity is the dissolution of the fibrin clot. The activation of plasminogen to plasmin occurs on the clot surface after binding to fibrin. Mediators of the activation are urokinase plasminogen activator (u-PA) or tissue-type plasminogen activator (t-PA).
Activation of the fibrinolytic process can be used to treat thrombotic conditions. Conversely, inhibition of fibrinolysis can be, and is, used for treatment of bleeding conditions. There are several possible targets for the inhibition of fibrinolysis. Activation of plasminogen activator inhibitor 1 (PAI-1), inhibition of u-PA and/or t-PA activity, inhibition of PLN activity and activation of antiplasmin are examples. Specific inhibition of proteolytic sites in tPA, uPA and PLN is difficult. However, bleeding control via inhibition of plasmin(ogen) fibrin binding by lysine analogues has been proven in humans as a safe and effective mechanism of action.
Inhibition of fibrinolysis via a lysine mimetic is a validated concept for reducing blood-loss, without increased risk for thrombotic complications, for instance following surgery, in menorrhagia, haemophilia and von Willebrands disease.
Potential uses of the compounds are to block plasmin-induced proteolysis as a universal pathomechanism propagating cancer, and cardiovascular, inflammatory, and many other diseases.
Antifibrinolytics have also been successfully used to treat hereditary angioedema. In this disease the skin or mucosa around the mouth, throat and tongue rapidly swell up. Swelling can occur at other places like limbs or genitals. For reasons that are not well-understood antifibrinolytics can be used as a prophylaxis or acute treatment of hereditary angioedema.
Tranexamic acid, currently the compound on the market to treat menorrhagia, requires very high and multiple doses and has gastrointestinal side effects. Its use has been described in “Tranexamic acid. A review of its use in surgery and other indications”; Dunn, C. J.; Goa K. L.; Drugs 1999, June 57 (6): 1005-1032.